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WO2006010082A1 - Naphtalenes disubstitues en position 1,4 utilises comme inhibiteurs de map kinase p38 - Google Patents

Naphtalenes disubstitues en position 1,4 utilises comme inhibiteurs de map kinase p38 Download PDF

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Publication number
WO2006010082A1
WO2006010082A1 PCT/US2005/024441 US2005024441W WO2006010082A1 WO 2006010082 A1 WO2006010082 A1 WO 2006010082A1 US 2005024441 W US2005024441 W US 2005024441W WO 2006010082 A1 WO2006010082 A1 WO 2006010082A1
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WO
WIPO (PCT)
Prior art keywords
compound
pro
fluoro
morpholin
naphthalen
Prior art date
Application number
PCT/US2005/024441
Other languages
English (en)
Inventor
Mark Antony Ashwell
Yanbin Liu
Syed Ali
Jason Hill
Woj Wrona
Original Assignee
Arqule, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Arqule, Inc. filed Critical Arqule, Inc.
Priority to US11/631,617 priority Critical patent/US7829560B2/en
Publication of WO2006010082A1 publication Critical patent/WO2006010082A1/fr
Priority to US12/854,687 priority patent/US8114873B2/en

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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
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    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D207/36—Oxygen or sulfur atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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    • C07D211/40—Oxygen atoms
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Definitions

  • cytokines participate in this response, including, but not limited to, IL-I, IL-6, IL-8 and TNF ⁇ . Although these cytokines are expressed in a normal response to many physiological stimuli, excess, unregulated, or otherwise aberrant production of these cytokines can lead to inflammation and tissue damage.
  • Diseases for example, inflammatory and autoimmune diseases such as rheumatoid arthritis, can mediate morbidity though such aberrant production of cytokines (Keffer, J., et al, EMBO J., 13: 4025-4031, 1991, Feldmann, M., et al, Annu. Rev.
  • p38 MAP Kinase also known as CSBP or SAPK, and hereinafter referred to as "p38" signaling pathway has been reported to be responsible for the expression of pro ⁇ inflammatory cytokines that are elevated in many inflammatory and autoimmune diseases (see, e.g., Dong, C, et al, Annu. Rev. Immunol., 20: 55-72, 2002; which is hereby incorporated by reference).
  • Inhibitors of any part of the p38 pathway or inhibitors of pathways that regulate the p38 pathway may be useful as therapeutics for diseases or conditions in which inflammation or autoimmune responses are involved. (Lee, J. C, et al, Immunopharm, 47: 185-201, 2000; which is hereby incorporated by reference).
  • the p38 pathway has been shown to be activated by cellular stressors, such as osmotic shock, UV light, free radicals, bacterial toxins, viruses, cytokines, and chemokines, to name a few, and in response, mediates the expression of several cytokines including, but not limited to, IL-I, IL-6, IL-8 and TNF ⁇ (Ono, K. and Han, J., Cellular Signalling, 12: 1-13, 2000; which is hereby incorporated by reference).
  • cellular stressors such as osmotic shock, UV light, free radicals, bacterial toxins, viruses, cytokines, and chemokines
  • the p38 pathway can be directly or indirectly activated by cell surface receptors, such as receptor tyrosine kinases, chemokine or G protein-coupled receptors, which have been activated by a specific ligand, e.g., cytokines, chemokines or lipopolysaccharide (LPS) binding to a cognate receptor.
  • cell surface receptors such as receptor tyrosine kinases, chemokine or G protein-coupled receptors, which have been activated by a specific ligand, e.g., cytokines, chemokines or lipopolysaccharide (LPS) binding to a cognate receptor.
  • LPS lipopolysaccharide
  • p38 can phosphorylate other intracellular proteins, including protein kinases, and can be translocated to the cell nucleus, where it can phosphorylate and activate transcription factors leading to the expression of pro-inflammatory cytokines and other proteins that contribute to the inflammatory response, cell adhesion, and proteolytic degradation.
  • pro-inflammatory cytokines and other proteins that contribute to the inflammatory response, cell adhesion, and proteolytic degradation.
  • cytokines and other proteins that contribute to the inflammatory response, cell adhesion, and proteolytic degradation.
  • myeloid lineage such as macrophages and monocytes
  • both IL-I and TNF ⁇ are transcribed in response to p38 activation.
  • Subsequent translation and secretion of these and other cytokines initiates a local or systemic inflammatory response in adjacent tissue and through infiltration of leukocytes.
  • autoimmune diseases and diseases associated with chronic inflammation, as well as acute responses have been linked to activation of p38, and activation of p38 in association with overexpression or dysregulation of other inflammatory cytokines.
  • diseases include, but are not limited to: rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram-negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; Huntingdon's disease; Parkinson's disease; acute
  • inhibitors of p38 activity that also inhibit excess or unregulated cytokine production and inhibitors that can inhibit more than a single pro-inflammatory cytokine may be useful as anti-inflammatory agents and therapeutics.
  • the present invention relates to compounds capable of inhibiting p38, methods for inhibiting p38 in vivo or in vitro, methods for treating conditions associated with p38 activity or cytokine activity, and to compounds useful for preparing the compounds of the invention.
  • the present invention provides compounds represented by Formula I:
  • X is O, NR, CH 2 , or a bond;
  • R is H or alkyl;
  • R' is H or alkyl; m is O, I, or 2; n is 0, I, or 2; p is 0, 1, 2, 3, or 4;
  • Ar is an aryl group
  • Het is a heterocyclic group
  • Yi is independently selected from the group consisting of halogen, alkyl, nitro, hydroxyl, and alkyloxy;
  • Y 2 is independently selected from the group consisting of halogen, alkyl, nitro, hydroxyl, and alkyloxy.
  • the compound is represented by the structure Formula Ib:
  • Ri is H or F;
  • R 3 and R 4 are independently selected from hydrogen, aliphatic or aromatic secondary or tertiary amine and secondary or tertiary amine with additional functional groups such as alcohols, sulfone, heterocyclic aromatic rings with tertiary amines, and aliphatic tertiary amines; and wherein R 3 and R 4 together may form a ring having from 3-8 heteroatoms in the ring.
  • the present invention provides pharmaceutical compositions comprising one or more compounds of Formula I, together with a pharmaceutically acceptable carrier.
  • the present invention provides methods for treating p38-associated conditions.
  • Methods of the present invention can include administering to the mammal an effective amount of compound of Formula I, such that the p38-associated condition is treated.
  • the p38-associated condition is rheumatoid arthritis, osteoarthritis or gouty arthritis (more preferably rheumatoid arthritis); Crohn's disease, ulcerative colitis, inflammatory bowel disease or psoriasis; or a proliferative disease, an autoimmune disease or an inflammatory disease.
  • the present invention provides methods for treating conditions associated with cytokine activity. These methods can include administering to a mammal an effective amount of compound of Formula I, such that a condition associated with altered cytokine activity is treated.
  • the cytokine-associated condition is rheumatoid arthritis, osteoarthritis or gouty arthritis; Crohn's disease, ulcerative colitis, inflammatory bowel disease or psoriasis; or a proliferative disease, an autoimmune disease or an inflammatory disease.
  • the invention provides methods for treating conditions associated with specific isoforms of p38, for example, p38 ⁇ , p38 ⁇ , p38 ⁇ , p38 ⁇ , or combinations of these.
  • p38 ⁇ is the specific isoform of p38.
  • the p38 ⁇ -associated condition is rheumatoid arthritis, osteoarthritis or gouty arthritis; Crohn's disease, ulcerative colitis, inflammatory bowel disease or psoriasis; or a proliferative disease, an autoimmune disease or an inflammatory disease.
  • the invention provides methods for treating conditions associated with or mediated by p38, other kinases, or p38 and other kinases.
  • the invention provides methods for treating disease conditions associated with one or more cytokines, where a cytokine is preferably selected from the group consisting of IL-I, IL-6, IL-8, and TNF ⁇ .
  • these methods include administering to a mammal or patient (e.g., a mammal in need of such treatment) an effective amount of a compound of Formula I, such that the mammal is treated.
  • a mammal or patient e.g., a mammal in need of such treatment
  • a preferred mammal is a human.
  • the present invention provides methods for inhibiting the activity of p38 in a cell, in vitro or in vivo.
  • these methods can include contacting a cell containing p38 with an effective p38-inhibiting amount of a compound of Formula I, under conditions such that p38 activity in the cell is inhibited.
  • the invention provides methods for characterizing p38 in a cell or tissue sample by determining, for example, the presence, location, or quantity of p38. These methods can include the steps of a) contacting the cell or tissue sample with a compound of Formula I under conditions such that the compound of Formula I can bind to p38 protein; and b) determining the presence, location and/or quantity of the compound of Formula I in the cell or tissue sample, thereby determining the presence, location and/or quantity of p38 protein in the cell or tissue sample.
  • one or more compound of Formula I may be combined with another agent, e.g., another pharmaceutically- active agent, for use in the inventive methods.
  • another agent e.g., another pharmaceutically- active agent
  • the present invention provides a method for preparing a compound of Formula I or a salt thereof.
  • the method can include reacting a compound of Formula II:
  • Ar is as described in Formula I; and Z is OH or a leaving group; under conditions such that a compound of Formula I is prepared.
  • the present invention provides compounds, pharmaceutical compositions, and methods useful for treatment of human and veterinary conditions related to p38 or cytokine activity or to p38 and cytokine activity or compounds, pharmaceutical compositions, and methods useful for treatment of human and veterinary conditions associated with p38 or cytokines or p38 and cytokines.
  • alkyl refers to radicals containing carbon and hydrogen, without unsaturation.
  • Alkyl radicals can be straight or branched.
  • Exemplary alkyl radicals include, without limitation, methyl, ethyl, propyl, isopropyl, hexyl, t-butyl, sec-butyl and the like.
  • a Ci - C 6 alkyl group is an alkyl group having from one to six carbon atoms in the straight or branched aikyl backbone.
  • Alkyl groups optionally can be substituted with one or more moieties such as hydroxyl group, carboxylate, oxo, halogen, thiol, cyano, nitro, amino, -NRi 2 Rn, Ci - C 6 alkylthio, arylthio, Ci - C 6 alkyl, Ci - C 6 alkoxy, aryloxy, alkylcarbonyloxy, arylcarbonyloxy, C 3 - C 6 cycloalkyl, C3 - C 6 cycloalkyloxy, C 2 - C 6 alkenyl, C 2 - C 6 alkynyl, aryl, aminocarbonyl, Ci - C 6 alkylcarbonyl, C 3 - C 6 cycloalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, aryloxycarbonyl, Ci - C 6 alkoxycarbonyl, C 3 - C 6 cycloalkyloxycarbonyl,
  • a “cycloalkyl” group refers to a cyclic alkyl group which has a ring having from three to seven carbon atoms in the ring portion.
  • a cycloalkyl group may be substituted with one or moieties as described for alkyl groups.
  • alkenyl refers to a hydrocarbon radical having at least one carbon-carbon double bond.
  • a C 2 - C 6 alkenyl group is an alkenyl group having from two to six carbon atoms in straight or branched alkenyl backbone.
  • Exemplary alkenyl radicals include, without limitation, vinyl, propenyl, 2-butenyl, and the like.
  • An alkenyl group may be substituted with one or moieties as described for alkyl groups.
  • alkynyl refers to a hydrocarbon radical having at least one carbon-carbon triple bond.
  • a C 2 - C 6 alkynyl group is an alkynyl group having from two to six carbon atoms in straight or branched alkynyl backbone.
  • Exemplary alkynyl moieties include propynyl, 3-hexynyl, and the like.
  • An alkynyl group may be substituted with one or moieties as described for alkyl groups.
  • aryl refers to an aromatic carbocyclic or heteroaromatic moiety, having one, two, or three rings.
  • An aryl group may be carbocyclic or may optionally contain from 1 — 4 heteroatoms (such as nitrogen, sulfur, or oxygen) in the aromatic ring.
  • exemplary aryl radicals include, without limitation, phenyl, naphthyl, pyridyl, pyrimidyl, triazyl, quinazolinyl, thiazolyl, benzothiophenyl, furanyl, imidazolyl, and the like.
  • An aryl group optionally can be substituted with one or more substituents such as hydroxyl group, halogen, thiol, cyano, nitro, amino, - NRi 2 Ri 3 , Ci - C 6 alkylthio, arylthio, Ci - C 6 alkyl, Ci - C 6 alkoxy, aryloxy, alkylcarbonyloxy, arylcarbonyloxy, C 3 - C 6 cycloalkyl, C 3 - C 6 cycloalkyloxy, C 2 - C 6 alkenyl, C 2 - C 6 alkynyl, aryl, carboxylate, aminocarbonyl, Ci - C 6 alkylcarbonyl, C 3 - C 6 cycloalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, aryloxycarbonyl, Ci - C 6 alkoxycarbonyl, C 3 - C 6 cycloalkyloxycarbonyl, heterocycl
  • heterocyclyl or “heterocycle” refers to a stable 3-8 membered monocyclic heterocyclic ring or 7-11 membered bicyclic heterocyclic ring which is either saturated or unsaturated (including aromatic), and may be fused, spiro or bridged to form additional rings.
  • Each ⁇ 'eterdcyc ⁇ e " consists of one'Or'more carbon atoms and from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • a heterocyclyl radical may be attached at any endocyclic atom which results in the creation of a stable structure.
  • Preferred heterocycles include 3-7 membered monocyclic heterocycles (more preferably 5-7-membered monocyclic heterocycles) and 8-10 membered bicyclic heterocycles.
  • groups include piperidinyl, pyranyl, pyridinyl, pyridonyl, tetrazolyl, triazolyl, piperazinyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfone, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, isoxozolyl, tetrahydropyranyl, tetrahydrofuranyl, dioxolyl, dioxinyl, oxathiolyl, benzodioxolyl, dithiolyl, thiophenyl, tetrahydrothiophenyl, sulfolanyl, dio
  • a heterocycle may optionally be substituted with one or more substituents as described above for alkyl groups, although an endocyclic oxygen may not be substituted, and an endocyclic nitrogen atom may be substituted with hydrogen, Ci - C 6 alkyl, C 3 - C 6 cycloalkyl, C 2 - Ce alkenyl, C 2 - C 6 alkynyl, aryl, aminocarbonyl, Cj - C 6 alkylcarbonyl, arylcarbonyl, aryloxycarbonyl, Ci - C 6 alkoxycarbonyl, Ci - C 6 alkylsulfonyl, arylsulfonyl, or a heterocyclyl group.
  • azacycle refers to an endocyclic-nitrogen-containing heterocycle as described above.
  • Preferred azacycles include (without limitation) substituted or unsubstituted pyrrolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, pyridinyl, triazolyl, tetrazolyl, quinuclidinyl (l-azabicyclo[2.2.2]octanyl), and tropanyl (8-methyl-8-azabicyclo[3.2.1]octanyl).
  • halogen refers to an atom selected from fluorine, chlorine, bromine, and iodine.
  • amino refers to a moiety represented by the formula - NRioRn, in which Rio and Rn are each independently selected from the group consisting of hydrogen, Ci - Ce alkyl, C 3 - C 6 cycloalkyl, aryl, and a heterocyclyl moiety; or Rio and Rn, together with the nitrogen atom to which they are both attached, form a 3-8 membered heterocyclic ring (which may be fused or bridged as described above for heterocyclyl moieties).
  • Preferred amino groups include -NH 2 , monoalkylamino (-NHCi - C 6 alkyl), dialkylamino (- N(Ci - C 6 alkyl) 2 ), monoarylamino (-NH-aryl), arylalkylamino (-N(aryl)(Ci - C 6 alkyl)), and the like.
  • Ri 2 is selected from the group consisting of hydrogen, Ci - Ce alkyl, and aryl.
  • Ri 3 is selected from the group consisting of -C(O)-Ci - C 6 alkyl, -C(O)-C 3 - C 6 cycloalkyl, -C(O)- aryl, -C(O)-heterocyclyl, -C(O)O-Cj - C 6 alkyl, -C(O)O-C 3 - C 6 cycloalkyl, -C(O)O-aryl, - C(O)O-heterocyclyl, -C(O)-amino, -SO 2 -Ci - C 6 alkyl, -SO 2 -C 3 - C 6 cycloalkyl -SO 2 -aryl, and -SO 2 -heterocyclyl.
  • the N-oxide form of any nitrogen atom is included in the compounds and methods of
  • X is O, NR, CH 2 , or a bond;
  • R is H or alkyl;
  • R' is H or alkyl; m is 0, 1, or 2; n is 0, 1, or 2; p is 0,1, 2, 3, or 4; Ar is an aryl group;
  • Het is a heterocyclic group
  • Yi is independently selected from the group consisting of halogen, alkyl, nitro, hydroxyl, and alkyloxy;
  • Y 2 is independently selected from the group consisting of halogen, alkyl, nitro, hydroxyl, and alkyloxy.
  • m is 1 or 2.
  • n 0.
  • p 0.
  • X is selected from the group consisting of CH 2 and oxygen.
  • Ar is a phenyl group.
  • the phenyl group is substituted with a group selected from the group consisting of:
  • Ar is disubstitued.
  • Ar is substituted with a fluorine group and a phenyl group, more preferably wherein the phenyl group is substituted with a group selected from the group consisting of
  • Het is selected from the group consisting of:
  • R 3 and R 4 are independently selected from hydrogen, aliphatic or aromatic secondary or tertiary amine, secondary or tertiary amine with additional functional groups such as alcohols, sulfone, heterocyclic aromatic rings with tertiary amines, and aliphatic tertiary amines; and wherein R 3 and R 4 together may form a ring having from 3-8 heteroatoms in the ring.
  • Het is selected from the group consisting of:
  • R- 3 and R 4 are independently selected from hydrogen, aliphatic or aromatic secondary or tertiary amine, secondary or tertiary amine with additional functional groups such as alcohols, sulfone, heterocyclic aromatic rings with tertiary amines, and aliphatic tertiary amines; wherein R 3 and R 4 together may form a ring having from 3-8 heteroatoms in the ring; and Ar is substituted with a fluorine group and a phenyl group, wherein the phenyl group is substituted with a group selected from the group consisting of
  • Ri is H or F
  • R 2 is selected from the group consisting of:
  • R 3 and R 4 are independently selected from hydrogen, aliphatic or aromatic secondary or tertiary amine and secondary or tertiary amine with additional functional groups such as alcohols, sulfone, heterocyclic aromatic rings with tertiary amines, and aliphatic tertiary amines; and wherein R 3 and R 4 together may form a ring having from 3-8 heteroatoms in the ring.
  • Compounds of Formula I can also include tracers, tags or labeling moieties, e.g., radioisotopes (such as tritium, carbon- 14, or sulfur-35), fluorescent labels, and the like, which are known to one of ordinary skill in the art. Such labeled compounds can be used in methods for detecting or determining the presence of p38 in a cell or a tissue type.
  • compounds of Formula I are selected to preserve the desired activity of the compounds (e.g., inhibition of cytokine activity, including inhibition of TNF ⁇ activity and IL-I activity, or inhibition of p38 activity).
  • substituents of a compound of Formula I should be selected to preserve such activity.
  • the substituent R' (attached to the amide nitrogen of a compound of Formula I) is hydrogen.
  • Preservation of activity can be determined using in vivo and in vitro assays such as the assays described elsewhere in this specification.
  • Preferred embodiments of the invention include, for example, compounds depicted as
  • a compound of the invention can inhibit phosphorylation of a substrate by p38 MAP Kinase in vitro or in vivo.
  • a compound of the invention inhibits phosphorylation of a substrate by p38 MAP Kinase in vitro.
  • the substrate is ATF2.
  • Inhibition of phosphorylation of a substrate by p38 MAP Kinase can be measured by any method known to the skilled artisan.
  • Inhibition of phosphorylation can be measured as the concentration of compound at which 50% inhibition of phosphorylation results (IC 5 o)- Inhibition of phosphorylation occurs at any concentration of compound where the phosphorylation of a substrate by p38 MAP Kinase is decreased in comparison to the pnospnoryrauon oi me suostra ⁇ e oyp38 MAP Kinase in the absence of the compound.
  • a compound exhibits an IC 50 value between about 0.0001 and about 100 ⁇ M (IC 50 ).
  • a compound of the invention has an IC50 value of between about 0.0001 and about 10 ⁇ M; more preferably the ICs 0 value is less than about 5 ⁇ M; more preferably less than about 2 ⁇ M; more preferably less than about 1 ⁇ M; and even more preferably less than about 0.1 ⁇ M.
  • a compound of the invention inhibits cytokine release in vitro or in vivo. In a preferred embodiment, a compound of the invention inhibits cytokine release in vitro. Inhibition of the release of any cytokine can be measured by any method known to the skilled artisan. Inhibition of cytokine release can be measured as the concentration of compound at which 50% inhibition of cytokine release results (IC 50 ). In a preferred embodiment, TNF ⁇ or IL- l ⁇ is inhibited or both TNF ⁇ and IL- l ⁇ are inhibited. Inhibition of cytokine release occurs at any concentration of compound where the cytokine release is decreased in comparison to the cytokine release in the absence of the compound.
  • a compound exhibits an IC 50 value between about 0.0001 and about 100 ⁇ M (IC 50 ).
  • IC 50 IC 50
  • a compound of the invention has an IC 50 value of between about 0.0001 and about 10 ⁇ M; more preferably the IC 50 value is less than about 5 ⁇ M; more preferably less than about 2 ⁇ M; more preferably less than about 1 ⁇ M; and even more preferably less than about 0.1 ⁇ M.
  • structures depicted herein are meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center, unless a particular stereochemistry is specifically indicated.
  • a salt of a compound of the present is a "pharmaceutically acceptable salt.”
  • a “pharmaceutically acceptable salt” means a salt which is, within the scope of sound medical judgment, suitable for pharmaceutical use in a patient without undue toxicity, irritation, allergic response, and the like, and effective for the intended use.
  • a prodrug is a compound that is metabolized in vivo (e.g., by a metabolic transformation such as deamination, dealkylation, de-esterification, and the like) to provide an active compound.
  • a "pharmaceutically acceptable prodrug” means a compound which is, within the scope of sound medical judgment, suitable for pharmaceutical use in a patient without undue toxicity, irritation, allergic response, and the like, and effective for the intended use, including a pharmaceutically acceptable ester as well as a zwitterionic form, where possible, of the compounds of the invention.
  • Examples of pharmaceutically-acceptable prodrug types contemplated by the present invention are described in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.
  • the compounds and compositions of the invention can also include metabolites.
  • metabolite means a product of metabolism of a compound of the invention or a pharmaceutically acceptable salt, analog, or derivative thereof, that exhibits a similar activity in vitro or in vivo to a compound of the invention.
  • the compounds and compositions of the invention can also include hydrates and solvates.
  • solvate refers to a complex formed by a solute (in this invention, a compound of Formula I and a solvent, for example).
  • solvents for the purpose of the invention preferably should not interfere with the biological activity of the solute.
  • Solvents may be, by way of example, water, ethanol, or acetic acid.
  • a method for synthesis can include reacting a compound of Formula II:
  • Z is OH or a leaving group; under conditions such that a compound of Formula I is prepared.
  • This amide-forming reaction can be performed under a range of conditions, some of which are known in the art, and may involve the use of coupling reagents, bases, or other reagents.
  • a wide variety of compounds of Formula III can be purchased from commercial vendors, or can be prepared according to methods known to one of ordinary skill in the art. Preparation of compounds of the invention is further described, for example, in the Examples and Schemes below.
  • the invention provides methods for treating disease conditions associated with (e.g., mediated directly or indirectly by) p38 or one or more cytokines.
  • the methods include administering to a subject in need of treatment (e.g., a mammal in need of such treatment) a therapeutically or prophylactically effective amount of a compound of the invention.
  • the compound of the invention can be a compound of Formula I.
  • the compound may be a compound of Formula Ia, Formula Ib, or any combination thereof.
  • a subject may include one or more cells or tissues, or organisms.
  • a preferred subject is a mammal.
  • a mammal may include any mammal.
  • preferred mammals include cattle, pigs, sheep, goats, horses, camels, buffalo, cats, dogs, rats, mice, and humans.
  • a highly preferred subject mammal is a human.
  • the compound(s) may be administered to the subject via any drug delivery route known in the art.
  • Specific exemplary administration routes include oral, ocular, rectal, buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intraveneous (bolus and infusion), intracerebral, transdermal, and pulmonary.
  • the invention provides methods for treating disease conditions in which p38 activity contributes to the disease phenotype.
  • the method includes administering a therapeutically or prophylactically effective amount of a compound of the invention to a subject in need thereof.
  • the compound of the invention can be a compound of Formula I or any combination of compounds of Formula I.
  • the compound may be a compound of Formula Ia or Formula Ib, or any combination thereof.
  • p38-associated condition means a disease or other deleterious condition in which the p38 MAP kinase signaling pathway is implicated, whether directly or indirectly. This includes, but is not limited to, conditions caused by IL-I, TNF ⁇ , IL-6 or IL-8 dysregulation or overexpression resulting from sustained, prolonged, enhanced or elevated levels of p38 activity.
  • Such conditions include, without limitation, inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, neurodegenerative diseases, allergies, reperfusion/ischemia in stroke, heart attacks, angiogenic disorders, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, thrombin-induced platelet aggregation, and conditions associated with the prostaglandin or cyclooxygenase and lipoxygenase signalling pathways, e.g., conditions involving prostaglandin endoperoxide synthase-2.
  • a p38-associated condition can include any condition associated with or mediated by an isoform of p38. In a preferred embodiment, the p38-associated condition is a condition associated with p38 ⁇ .
  • modulating p38 activity means increasing or decreasing p38 activity, whether in vitro or in vivo. Modulating p38 activity preferably means decreasing (inhibiting) p38 activity. In certain preferred embodiments, p38 activity in a cell is inhibited by at least 20%, more preferably at least 30%, 40%, 50%, 80%, 90%, 95%, or 99% compared to the p38 activity of an untreated control cell, tissue or organism. In preferred embodiments, p38 activity in"a CeIf(Or ttSS'ue of organism/ ls'restored to a normal range for the cell (or tissue or organism) type upon treatment according to the methods of the invention.
  • the invention provides methods for treating disease conditions associated with a cytokine or cytokines.
  • the method includes administering a therapeutically or prophylactically effective amount of a compound of the invention to a subject in need thereof.
  • the compound of the invention can be a compound of Formula I.
  • the compound may be a compound of Formula Ia, Formula Ib, or any combination thereof.
  • at least one of the cytokine or cytokines is preferably selected from the group consisting of IL-I, IL-6, IL-8, and TNF ⁇ .
  • all of the cytokine or cytokines are selected from the group consisting of IL-I, IL-6, IL-8, and TNF ⁇ .
  • the methods include administering to a subject in need of treatment (e.g., a mammal in need of such treatment) an effective amount of a compound of the invention.
  • a condition associated with altered cytokine activity refers to a condition in which cytokine activity is altered compared to a non-diseased state. This includes, but is not limited to, conditions caused by IL-I, TNF ⁇ , IL-6 or IL-8 overproduction or dysregulation resulting in sustained, prolonged, enhanced or elevated levels of cytokine activity, which may be associated with p38 activity.
  • Such conditions include, without limitation, inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, neurodegenerative diseases, allergies, reperfusion/ischemia in stroke, heart attacks, angiogenic disorders, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, thrombin-induced platelet aggregation, and conditions associated with the prostaglandin or cyclooxygenase and lipoxygenase signaling pathways, such as prostaglandin endoperoxide synthase-2.
  • a cytokine-associated condition can include any condition associated with or mediated by IL-I (particularly IL-I ⁇ ), TNF ⁇ , IL-6 or IL-8, or any other cytokine which can be regulated by p38.
  • the cytokine-associated condition is a condition associated with TNF ⁇ .
  • terapéuticaally effective amount refers to any amount of a compound of the invention sufficient to treat a disease or condition, including preventing a disease or condition, ameliorating symptoms, slowing progression, reversing damage, ameliorating the disease or condition, or a combination thereof, or to exhibit a detectable therapeutic, prophylactic, or inhibitory effect.
  • the effect can be detected by, for example, the assays disclosed in the following examples.
  • the precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; ariclthe ihera ⁇ etfflc 11 of combination of therapeutics selected for administration.
  • Therapeutically and prophylactically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • the therapeutically or prophylactically effective amount can be estimated initially either in cell culture assays, e.g. , of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, pigs, or primates.
  • the animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
  • Therapeutic/prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., EDs 0 (the dose therapeutically effective in 50% of the population) and LD 50 (the dose lethal to 50% of the population).
  • the dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, EDso/LDso.
  • Pharmaceutical compositions that exhibit large therapeutic indices are preferred.
  • the data obtained from cell culture assays and animal studies may be used in formulating a range of dosages for human use.
  • the dosage contained in such compositions is preferably within a range of circulating concentrations that include an ED 5 O with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
  • the initial target plasma concentration may range from approximately 10 ng/mL to approximately 100 ⁇ g/mL, preferably from approximately 10 ng/mL to approximately 10 ⁇ g/mL, more preferably from approximately 10 ng/mL to approximately 1 ⁇ g/mL.
  • the compounds of the invention may be administered at doses that vary from 0.1 ⁇ g to 100,000 mg, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and is generally available to practitioners in the art.
  • the dose will be in the range of about lmg/day to about 10g/day, or about O.lg to about 3g/day, or about 0.3g to about 3g/day, or about 0.5g to about 2g/day, in single, divided, or continuous doses for a patient weighing between about 40 to about 100 kg (which dose may be adjusted for patients above or below this weight range, particularly children under 40 kg).
  • the exact dosage can be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage and administration are adjusted to provide sufficient levels of the active agent or agents or to maintain the desired effect.
  • Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination or combinations, reaction sensitivities, and tolerance/response to therapy. Long-acting phSrn ⁇ ace'utic'a ⁇ c ⁇ fnUxji&iti ⁇ nStti'jy'ftAdministered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.
  • the inventive methods can also be used to treat autoimmune diseases and diseases associated with acute and chronic inflammation.
  • diseases include, but are not limited to: rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram-negative sepsis; toxic shock syndrome; myofacial pain syndrome (MPS); Shigellosis; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; glomerular nephritis; scleroderma; chronic thyroiditis; Grave's disease; autoimmune gastritis; myasthenia gravis; autoimmune hemolytic anemia; autoimmune neutropenia; thrombocytopenia; pancreatic fibrosis; chronic active hepatitis including hepatic
  • the methods of the invention can be used to treat proliferative disorders (including both benign and malignant hyperplasias), including acute myelogenous leukemia, chronic myelogenous leukemia, Kaposi's sarcoma, metastatic melanoma, multiple myeloma, breast cancer, including metastatic breast carcinoma; colorectal carcinoma; malignant melanoma; gastric cancer; non-small cell lung cancer (NSCLC); bone metastases, and the like; pain disorders including neuromuscular pain, headache, cancer pain, dental pain, and arthritis pain; angiogenic disorders including solid tumor angiogenesis, ocular neovascularization, and infantile hemangioma; conditions associated with the cyclooxygenase and lipoxygenase signaling pathways, including conditions associated with prostaglandin endoperoxide synthase- 2 (including edema, fever, analgesia, and pain); organ hypoxia; thrombin-induced platelet aggregation.
  • treatment according to the invention includes preventing a disease or condition, ameliorating symptoms, slowing progression, reversing damage, ameliorating a disease or condition, or a combination thereof.
  • treating a disease condition associated with p38 or one or more cytokines results in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects.
  • the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and even more preferably by more than 120 days.
  • An increase in survival time of a population may be measured by any reproducible means.
  • an increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • an increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • treating a disease condition associated with p38 or one or more cytokines results in a decrease in the mortality rate of a population of treated subjects in comparison to a population of subjects receiving carrier alone.
  • treating a disease condition associated with p38 or one or more cytokines results in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population.
  • treating a disease condition associated with p38 or one or more cytokines results a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the present invention, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof.
  • the mortality rate is decreased by more than 2%; more preferably, by more than 5%; more preferably, by more than 10%; and most preferably, by more than 25%.
  • a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means.
  • a decrease in the mortality rate of a population may be measured, for example, by calculating for a population the average number of disease- related deaths per unit time following initiation of treatment with an active compound.
  • a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with an active compound.
  • treating a disease condition associated with p38 or one or more cytokines results in a decrease in growth rate of a tumor.
  • tumor growth rate is reduced by at least 5% relative to the tumor growth rate prior to treatment; more preferably, tumor growth rate is reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 60%; and most preferably, reduced by at least 75%.
  • Tumor growth rate may be measured by any reproducible means of measurement. In a preferred aspect, tumor growth rate is measured according to a change in tumor diameter per unit time.
  • tumor regrowth is less than 5%; more preferably, tumor regrowth is less than 10%; more preferably, less than 20%; more preferably, less than 30%; more preferably, less than 40%; more preferably, less than 50%; even more preferably, less than 60%; and most preferably, less than 75%.
  • Tumor regrowth may be measured by any reproducible means of measurement. In a preferred aspect, tumor regrowth is measured, for example, by measuring an increase in the diameter of a tumor after a prior tumor shrinkage that followed treatment.
  • a decrease in tumor regrowth is indicated by failure of tumors to reoccur after treatment has stopped.
  • treating a disease condition associated with p38 or one or more cytokines results in a reduction in the rate of cellular proliferation.
  • the rate of cellular proliferation is reduced by at least 5%; more preferably, by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 60%; and most preferably, by at least 75%.
  • the rate of cellular proliferation may be measured by any reproducible means of measurement.
  • the rate of cellular proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.
  • treating a disease condition associated with p38 or one or more cytokines results in a reduction in the proportion of proliferating cells.
  • the proportion of proliferating cells is reduced by at least 5%; more preferably, by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 60%; and most preferably, by at least 75%.
  • the proportion of proliferating cells may be measured by any reproducible means of measurement.
  • the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of noridividirig cells in a tissue sample. '
  • the proportion of proliferating cells is equivalent to the mitotic index.
  • treating a disease condition associated with p38 or one or more cytokines results in a decrease in size of an area or zone of cellular proliferation.
  • size of an area or zone of cellular proliferation is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 60%; and most preferably, reduced by at least 75%.
  • Size of an area or zone of cellular proliferation may be measured by any reproducible means of measurement.
  • size of an area or zone of cellular proliferation may be measured as a diameter or width of an area or zone of cellular proliferation.
  • treating a disease condition associated with p38 or one or more cytokines results in a decrease in inflammation.
  • the size of an area of inflammation is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 60%; and most preferably, reduced by at least 75%.
  • Size of an area of inflammation may be measured by any reproducible means of measurement. In a preferred aspect, size of an area of inflammation may be measured as a diameter or width of the area of inflammation.
  • the methods of the present invention may include identifying a subject in need of treatment.
  • the methods include identifying a mammal in need of treatment.
  • the methods include identifying a human in need of treatment. Identifying a subject in need of treatment may be accomplished by any means that indicates a subject who may benefit from treatment. For example, identifying a subject in need of treatment may occur by clinical diagnosis, laboratory testing, or any other means known to one of skill in the art, including any combination of means for identification.
  • the compounds of the invention may be formulated in pharmaceutical compositions, if desired, and can be administered by any route that permits treatment of the disease or condition.
  • a preferred route of administration is oral administration. Administration may take the form of single dose administration, or the compound of the invention can be administered over a period of time, either in divided doses or in a continuous- release formulation or administration method (e.g., a pump).
  • the compounds of the invention are administered to the subject, the amounts of compound administered and the route of administration " chosen should be 'selected to permit efficacious treatment of the disease condition.
  • the methods of the invention also include the use of a compound or compounds of the invention together with one or more additional therapeutic agents for the treatment of disease conditions.
  • the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, in combination with other pharmaceutically active agents in the treatment of disease.
  • Pharmaceutically active agents include any pharmaceutical agents that are useful for the treatment of any disease condition.
  • the compounds of the invention are pharmaceutically active agents that can be combined with other pharmaceutically active agents for the treatment of rheumatoid arthritis.
  • Such other pharmaceutically active agents include, but are not limited to: matrix metalloprotease inhibitors and other DMARDs (disease-modifying anti-rheumatic drugs) such as methotrexate, sulfasalazine, hydroxychloroquine, penicillamine, cyclosporin A, gold sodium thiomalate, auroanofin and aurothioglucose; CD8 antagonists; anti-TNF ⁇ agents; immunosuppressants and NSAIDs (non ⁇ steroidal anti-inflammatories).
  • matrix metalloprotease inhibitors and other DMARDs disease-modifying anti-rheumatic drugs
  • DMARDs disease-modifying anti-rheumatic drugs
  • methotrexate such as methotrexate, sulfasalazine, hydroxychloroquine, penicillamine, cyclosporin A, gold sodium thiomalate, auroanofin and aurothioglucose
  • the combination of active ingredients may be: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) delivered by any other combination therapy regimen known in the art.
  • the methods of the invention may comprise administering or delivering the active ingredients sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e., serially
  • simultaneous therapy effective dosages of two or more active ingredients are administered together.
  • Various sequences of intermittent combination therapy may also be used.
  • methods are provided for inhibiting the activity of p38 in a cell, in vitro or in vivo.
  • the methods include contacting a cell or tissue containing p38 with an effective p38-inhibiting amount of a compound of the invention, under conditions such that p38 activity in the cell or tissue is inhibited.
  • Contacting a cell refers to a condition in which a compound or other composition of matter is in direct contact with a cell or tissue, or is close enough to induce a desired biological effect in a cell or tissue.
  • contacting a cell or tissue containing p38 with a compound of the invention may be conducted by any means that permits an interaction between p38 and the compound of the invention, resulting in the desired biological effect in a cell.
  • Contacting a cell or tissue may be accomplished, for example, by introduction of a compound of the invention such as a Formula I compound, prodrug or intermediate. Contacting a cell or tissue may be accomplished by introduction of a pharmaceutical composition. Contacting a cell or tissue may be accomplished by direct introduction of the active compound to the cell or tissue containing p38.
  • a compound of the invention such as a Formula I compound, prodrug or intermediate.
  • Contacting a cell or tissue may be accomplished by introduction of a pharmaceutical composition.
  • Contacting a cell or tissue may be accomplished by direct introduction of the active compound to the cell or tissue containing p38.
  • contacting a cell or tissue may be accomplished by introducing a compound in a manner that the compound will be targeted, directly or indirectly, to a cell or ' tissue containing p38.
  • Contacting a cell or tissue may be accomplished under conditions such that a compound of the invention, preferably Formula I, can bind to p38 protein.
  • Such conditions may include proximity of the compound and p38 -containing cell or tissue, pH, temperature, or any condition that affects the binding of a compound of the invention to p38 protein.
  • the invention provides a method for modulating p38 activity in a cell or secreted by a cell.
  • the method includes contacting a cell containing p38 with an effective p38 -inhibiting amount of a compound of the invention, under conditions such that p38 activity in the cell is modulated (more preferably, inhibited).
  • the cell is contacted with the compound of the invention in vitro; in other embodiments, the cell is contacted with the compound of the invention in vivo.
  • the compound of the invention is provided in the form of a pharmaceutical composition, together with a pharmaceutically acceptable carrier.
  • the invention provides a method for modulating cytokine activity or levels in a cell.
  • the method includes contacting a cell containing cytokines with an effective cytokine-inhibiting amount of a compound of the invention, under conditions such that cytokine activity or levels in the cell are modulated (more preferably, inhibited).
  • the cell is contacted with the compound of the invention in vitro; in other embodiments, the cell is contacted with the compound of the invention in vivo,
  • the compound of the invention is provided in the form of a pharmaceutical composition, together with a pharmaceutically acceptable carrier.
  • the invention provides methods for determining whether a compound of Formula I is potentially useful as a therapeutic agent for the treatment of p38- or cytokine- associated conditions.
  • the methods comprise contacting p38 with a compound of the invention, and determining whether the compound of the invention modulates (preferably, inhibits) the activity of p38.
  • the methods comprise contacting p38 with a compound of the invention, and determining whether the compound of the invention modulates (preferably, inhibits) the activity of cytokines.
  • the contacting step takes place in vitro; in certain preferred embodiments, the contacting step comprises contacting a cell comprising p38 with a compound of Formula I.
  • the methods of the invention have many uses. For example, methods of inhibiting p38 activity in vitro may be useful, e.g., in developing screening assays (e.g., as a positive control), or as a research or diagnostic tool for studying the role of p38 in cellular function (e.g., inhibiting p38 to determine the effect of such inhibition on other functions in the cell).
  • methods of inhibiting p38 activity in vitro may be useful, e.g., in developing screening assays (e.g., as a positive control), or as a research or diagnostic tool for studying the role of p38 in cellular function (e.g., inhibiting p38 to determine the effect of such inhibition on other functions in the cell).
  • compounds of the invention in which the compounds contain a label or tag such as a radioisotope or a fluorescent label.
  • Such labeled compounds can be used in methods for detecting or determining the presence, activity or distribution of p38 in a cell or a tissue type, e.g., by contacting a cell or tissue with a labeled compound of the invention, and then detecting the presence or absence of the label in the cell or tissue.
  • tissue biopsy sample can be taken from a subject suffering from a p38-associated or cytokine-associated condition.
  • the biopsy sample can be tested to determine the level of p38 activity (or cytokine levels) present in the sample; the sample can then be contacted with a compound of the invention, and the p38 activity (or cytokine levels) measured to determine whether the compound of Formula I has a desired effect (e.g., inhibition of p38 or cytokine activity).
  • a desired effect e.g., inhibition of p38 or cytokine activity
  • the sample could be contacted with a labeled compound of the invention (e.g., a fluorescently-labeled compound) and the sample then examined (e.g., under a confocal microscope) to determine the distribution of p38 in the tissue sample.
  • a labeled compound of the invention e.g., a fluorescently-labeled compound
  • the sample then examined (e.g., under a confocal microscope) to determine the distribution of p38 in the tissue sample.
  • Repeated biopsy samples taken during a course of treatment could also be used to study the efficacy of the treatment.
  • Other diagnostic tests using the compounds of the invention will be apparent to one of ordinary skill in the art in light of the teachings of this specification.
  • the invention provides methods for determining the presence, location, or quantity, or any combination thereof of p38 protein in a cell or tissue sample.
  • the methods include a) contacting the cell or tissue sample with a compound of the invention under conditions such that the compound can bind to p38 protein; and b) determining the presence, location, or quantity, or any combination thereof of the compound of the invention in the cell or tissue sample, thereby determining the presence, location, or quantity, or any combination thereof of p38 protein in the cell or tissue sample. Determining the presence, location, or quantity, or any combination thereof of the compound of the invention in the cell or tissue sample may be conducted by any means that reveals the presence, location, or quantity, or any combination thereof of the compound in the cell or tissue. For example, as described previously, radioactive or fluorescent labeling methods may be used. Additional methods of determining the presence, location, or quantity, or any combination thereof of a compound of the invention will be apparent to a skilled artisan.
  • the invention provides methods for determining (1) whether a compound of the invention will be a useful therapeutic agent for treatment of a subject suffering from a p38-associated condition, or (2) the severity of disease or (3) the course of disease during treatment with a disease-modifying agent.
  • the methods include: a) obtaining a cell or tissue sample from the subject before, during and after termination of treatment with a compound of the invention or another disease-modifying agent; b) contacting the sample with a compound of the invention; and c) determining the amount of the compound of the invention that binds to the sample, wherein binding to p38 protein by the compound is related to the amount of p38 protein in the sample.
  • the invention provides methods for determining (1) whether a compound of the invention will be a useful therapeutic agent for treatment of a subject suffering from a cytokine-associated condition, or (2) the severity of disease or (3) the course of disease during treatment with a disease-modifying agent.
  • the methods include: a) obtaining a cell or tissue sample from the subject before, during and after termination of treatment with a compound of the invention or another disease-modifying agent; b) contacting the sample with a compound of the invention and c) determining the amount of the compound of the invention that binds to the sample, wherein binding to p38 protein by the compound is related to the amount of p38 protein in the sample, and the amount of p38 in the sample is related to the quantity of cytokines released.
  • such a method may be conducted by obtaining cells from a cancer cell line, contacting cells from the cancer cell line, such as, for example, cells from a metastatic breast carcinoma, colorectal carcinoma, malignant melanoma, gastric cancer, or non-small cell lung cancer line with a compound of the present invention and determining the binding.
  • a cancer cell line such as, for example, cells from a metastatic breast carcinoma, colorectal carcinoma, malignant melanoma, gastric cancer, or non-small cell lung cancer line with a compound of the present invention and determining the binding.
  • compositions useful in the methods of the invention are provided. More particularly, the pharmaceutical compositions of the invention may be useful, inter alia, for treating conditions associated with p38 activity or cytokine activity or any combination thereof.
  • a pharmaceutical composition contains an amount of a compound of the invention sufficient to achieve an intended therapeutic effect.
  • a pharmaceutical composition is any composition that may be administered in vitro or in vivo or both to a subject in order to treat a disease or condition by preventing a disease or condition, ameliorating symptoms, slowing progression, reversing damage, ameliorating a disease or condition, or a combination thereof.
  • a pharmaceutical composition may be administered m vivo.
  • a subject may include one or more cells or tissues, or organisms.
  • a preferred subject is a mammal.
  • a mammal includes any mammal, such as by way of non-limiting example, cattle, pigs, sheep, goats, horses, camels, buffalo, cats, dogs, rats, mice, and humans.
  • a highly preferred subject mammal is a human.
  • the pharmaceutical compositions of the invention may be formulated with pharmaceutically acceptable excipients such as carriers, solvents, stabilizers, adjuvants, diluents, etc., depending upon the particular mode of administration and dosage form.
  • the pharmaceutical compositons of the invention may optionally include one or more ingredients such as preservatives, absorption promoters to enhance bioavailability, fluorocarbons, other solubilizing or dispersing agents or any combination of such ingredients.
  • the pharmaceutical compositions should generally be formulated to achieve a physiologically compatible pH, and may range from a pH of about 3 to a pH of about 11, preferably about pH 3 to about pH 7, depending on the formulation and route of administration. In alternative embodiments, it may be preferred that the pH is adjusted to a range from about pH 5.0 to about pH 8.0. More particularly, the pharmaceutical compositions of the invention comprise a therapeutically or prophylactically effective amount of at least one compound of the present invention, together with one or more pharmaceutically acceptable excipients.
  • the pharmaceutical compositions of the invention may comprise a combination of compounds of the present invention, or may include a second active ingredient useful in the treatment or prevention of bacterial infection (e.g., anti-bacterial or anti-microbial agents).
  • Formulations of the present invention are most typically solids, liquid solutions, emulsions or suspensions, while inhaleable formulations for pulmonary administration are generally liquids or powders, with powder formulations being generally preferred.
  • a preferred pharmaceutical composition of the invention may also be formulated as a lyophilized solid that is reconstituted with a physiologically compatible solvent prior to administration.
  • Alternative pharmaceutical compositions of the invention may be formulated as syrups, creams, ointments, tablets, and the like.
  • pharmaceutically acceptable excipient refers to an excipient for administration of a pharmaceutical agent, such as the compounds of the present invention.
  • the term refers to any pharmaceutical excipient that may be administered without undue toxicity.
  • Pharmaceutically acceptable excipients are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition. Accordingly, there exists a wide variety of suitable formulations of pharmaceutical compositions of the present invention (see, e.g., Remington's Pharmaceutical Sciences).
  • Suitable excipients may be carrier molecules that include large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virus particles.
  • excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA; carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid; liquids such as oils, water, saline, glycerol and ethanol; wetting or emulsifying agents; pH buffering substances; and the like.
  • antioxidants such as ascorbic acid
  • chelating agents such as EDTA
  • carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid
  • liquids such as oils, water, saline, glycerol and ethanol
  • wetting or emulsifying agents such as oils, water, saline, glycerol and ethanol
  • wetting or emulsifying agents pH buffering substances; and the like.
  • liposomes are also included within the definition of pharmaceutically acceptable excipients.
  • compositions of the invention may be formulated in any form suitable for the intended method of administration.
  • tablets, troches, lozenges, dragees, aqueous or oil suspensions, non-aqueous solutions, dispersible powders or granules (including micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs, for example may be prepared.
  • Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents including preserving agents or sweetening agents, flavoring agents, and coloring agents, in order to provide a palatable preparation.
  • compositions particularly suitable for use in conjunction with tablets include, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as croscarmellose sodium, cross-linked povidone, maize starch, or alginic acid; binding agents, such as povidone, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • inert diluents such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate
  • disintegrating agents such
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example celluloses, lactose, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with non ⁇ aqueous or oil medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example celluloses, lactose, calcium phosphate or kaolin
  • non ⁇ aqueous or oil medium such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.
  • pharmaceutical compositions of the invention may be formulated as suspensions comprising a compound of the present invention in admixture with at least one pharmaceutically acceptable excipient suitable for the manufacture of a suspension.
  • pharmaceutical compositions of the invention may be formulated as dispersible powders and granules suitable for preparation of
  • Excipients suitable for use in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate); and thickening agents, such as carbomer, beeswax, hard paraffin or cetyl alcohol.
  • suspending agents such as sodium carboxymethylcellulose
  • the suspensions may also contain one or more preservatives such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
  • preservatives such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate
  • coloring agents such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate
  • flavoring agents such as sucrose or saccharin.
  • sweetening agents such as sucrose or saccharin.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally-occuring gums, such as gum acacia and gum tragacanth; naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids; hexitol anhydrides, such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • sweetening agents such as glycerol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous emulsion or oleaginous suspension.
  • This emulsion or suspension may be formulated according to the known art using any suitable dispersing or wetting agents and suspending agents such as those mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1 ,2-propane-diol.
  • the sterile injectable preparation may also be prepared as a lyophilized powder.
  • thaV may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile fixed oils may be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • a pharmaceutically acceptable salt of a compound of the invention may be dissolved in an aqueous solution of an organic or inorganic acid, such as for example, a 0.3 M solution of succinic acid, or more preferably, citric acid.
  • an organic or inorganic acid such as for example, a 0.3 M solution of succinic acid, or more preferably, citric acid.
  • the compound of formula (I) may be dissolved in a suitable co-solvent or combination of co- solvents.
  • suitable co-solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0 to 60% of the total volume.
  • the active compound of Formula I is dissolved in DMSO and diluted with water.
  • the pharmaceutical composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle, such as for example, water or isotonic saline or dextrose solution.
  • an appropriate aqueous vehicle such as for example, water or isotonic saline or dextrose solution.
  • compounds which have been modified by substitutions or additions of chemical or biochemical moieties which make them more suitable for delivery e.g , increase solubility, bioactivity, palatability, decrease adverse reactions, etc ), for example by esterification, glycosylation, PEGylation, etc.
  • the compounds of the present invention may be formulated for oral administration in a lipid-based formulation suitable for low solubility compounds. Lipid-based formulations can generally enhance the oral bioavailability of such compounds.
  • a preferred pharmaceutical composition of the invention comprises a therapeutically or prophylactically effective amount of a compound of the present invention, together with at least one pharmaceutically acceptable excipient selected from the group consisting of: medium chain fatty acids or propylene glycol esters thereof (e.g., propylene glycol esters of edible fatty acids such as caprylic and capric fatty acids) and pharmaceutically acceptable surfactants such as polyoxyl 40 hydrogenated castor oil.
  • a pharmaceutically acceptable excipient selected from the group consisting of: medium chain fatty acids or propylene glycol esters thereof (e.g., propylene glycol esters of edible fatty acids such as caprylic and capric fatty acids) and pharmaceutically acceptable surfactants such as polyoxyl 40 hydrogenated castor oil.
  • cyclodextrins may be added as aqueous solubility enhancers.
  • Preferred cyclodextrins include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ⁇ -, ⁇ -, and ⁇ -cyclodextrin.
  • a particularly preferred cyclodextrin solubility enhancer is hydroxypropyl- ⁇ -cyclodextrin (HPBC), which may be added to any of the above-described compositions to further improve the aqueous solubility characteristics of the compounds of the present invention.
  • the composition comprises 0.1% to 20% hydroxypropyl- ⁇ -cyclodextrin, more preferably 1 % to 15% hydfoxypfopyr- ⁇ -cy ⁇ i ⁇ ' a ' exWn' a ⁇ d ' Bvfen more preferably from 2.5% to 10% hydroxypropyl- ⁇ - cyclodextrin.
  • solubility enhancer employed will depend on the amount of the compound of the present invention in the composition.
  • compositions of the invention may be formulated for administration by inhalation.
  • a pharmaceutical composition of the present invention may be formulated as a powdered mix containing a compound of the invention and a suitable powder base such as lactose or starch for example.
  • Such pharmaceutical compositions can be delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • compositions are prepared for topical application.
  • Pharmaceutical compositions for topical administration can be formulated in a suitable ointment containing the active component suspended or dissolved in one or more excipients.
  • Excipients for topical administration of the compounds of this invention can include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • pharmaceutical compositions of the present invention can be formulated in a suitable lotion or cream containing active components of the present invention suspended or dissolved in one or more pharmaceutically acceptable excipients.
  • Suitable excipients can include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2- octyldodecanol, benzyl alcohol and water.
  • the compounds of the invention can also be formulated in pharmaceutical compositions suitable for rectal administration such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • a pharmaceutical composition contains a total amount of the active ingredient or ingredients sufficient to achieve an intended therapeutic effect. More specifically, in some embodiments, the pharmaceutical composition contains a therapeutically effective amount of a p38-inhibiting compound of the invention (i.e., an amount of a p38-inhibiting compound of the invention that is effective in the prevention or treatment of the existing symptoms of a disease or condition associated with or mediated directly or indirectly by p38).
  • a therapeutically effective amount of a p38-inhibiting compound of the invention i.e., an amount of a p38-inhibiting compound of the invention that is effective in the prevention or treatment of the existing symptoms of a disease or condition associated with or mediated directly or indirectly by p38.
  • the pharmaceutical composition contains a therapeutically effective amount of a cytokine- inhibiting compound of the invention (i.e., an amount effective to prevent development of or to alleviate the existing symptoms of a disease or condition associated with a cytokine or cytokines, such as, but not limited to, IL-I, IL-6, IL-8 and TNF ⁇ ).
  • a cytokine- inhibiting compound of the invention i.e., an amount effective to prevent development of or to alleviate the existing symptoms of a disease or condition associated with a cytokine or cytokines, such as, but not limited to, IL-I, IL-6, IL-8 and TNF ⁇ .
  • the total amounts of the compound of the Invention that iri'ay" bfe combined with the carrier materials to produce a unitary dosing form will vary depending upon the host treated and the particular mode of administration.
  • compositions are formulated so that a dose of between about 0.0001 to 100 mg/kg body weight/day of a p38-inhibiting agent or cytokine-inhibiting agent or both 38- and cytokine-inhibiting agent is administered to a patient receiving the compositions.
  • compositions of the present invention may also be prepared for sustained release.
  • sustained-release materials have been established and are known by those skilled in the art.
  • Sustained-release pharmaceutical compositions can, depending on their chemical nature, release a compound of the invention for a period of a few hours, a few days or weeks up to over 100 days.
  • Examples of compounds of the invention represented by Formula I can be prepared according to the following representative methods.
  • Compound B45 N-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-pyrrolidin-l-yl-isonicotinamide (Compound B45).
  • Compound is formed by reacting 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-isonicotinamide and pyrrolidine under conditions described in general procedure A.
  • reaction mixture is diluted with CHCl 3 (5 ml) and washed with saturated NaHCO 3 solution (5 ml), water (5 ml), and dried with sodium sulfate. The organic layer is then evaporated to dryness. The residue is purified by column chromatography on silica gel (1-2% methanol in CH 2 Cl 2 ) to give 3-fluoro-N-(4- ⁇ [2- (methylsulfonyl)pyrimidin-4-yl]oxy ⁇ -l-naphthyl)-5-morpholin-4-ylbenzamide as a white solid.
  • Ethyl-4-[4-( ⁇ 4-[(3-fluoro-5-morpholin-4-ylbenzoyl)amino]-l-naphthyl ⁇ oxy)pyrimidin-2- yl]piperazine-l-carboxylate (Compound B329).
  • Compound is prepared from 3-fluoro-N-(4- ⁇ [2-(methylsulfonyl)pyrimidin-4-yl]oxy ⁇ -l -naphthyl)-5-morpholin-4-ylbenzamide and piperazine-1-carboxylic acid ethyl ester according to conditions described in general procedure C.
  • Compound B347 Compound is prepared from 3- fluoro-N-(4- ⁇ [2-(methylsulfonyl)pyrimidin-4-yl]oxy ⁇ -l-naphthyl)-5-mo ⁇ holin-4-ylbenzamide and l,l-Dioxo-tetrahydro-l ⁇ 6-thiophen-3-ylamine according to conditions described in general procedure C.
  • Compound is prepared from 3-fluoro- ⁇ -[4-(2- methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-l-yl]-5-piperidin-l-yl-benzamide (obtained from /-butyl (4- ⁇ [2-(methylthio)pyrimidin-4-yl]oxy ⁇ -l-naphthyl)carbamate and 3-fluoro-5- piperidinylbenzoic acid according to conditions described in Example 3, Steps 3 and 4 and isopr ⁇ ylamine ' acc ⁇ rdihg tb conditions described in general procedure C.
  • Ethyl 4-[4-( ⁇ 4-[(3-fluoro-5-piperidin-l-ylbenzoyI)amino]-l-naphthyl ⁇ oxy)pyrimidin-2- yl]piperazine-l-carboxylate (Compound B376).
  • Compound is prepared from 3-fluoro-N-[4- (2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-l-yl]-5-piperidin-l-yl-benzamide and piperazine-1-carboxylic acid ethyl ester according to conditions described in general procedure C.
  • 3-Vlubrb 5-p ⁇ per ⁇ din-l-yl-N- ⁇ 4-[(2-pyrrolidin-l-ylpyrimidiii-4-yl)oxy]-l- naphthyl ⁇ benzamide (Compound B377).
  • Compound is prepared from 3-fluoro-N-[4-(2- methanesulfonyl-pyrimidin-4-yloxy)-naphthalen- 1 -yl]-5-piperidin- 1 -yl-benzamide and pyrrolidine according to conditions described in general procedure C.
  • Compound B222 Compound is prepared from tert-bxatyX (4-hydroxy-l-naphthyl)carbamate and 3-pyridin-3-yl-propan-l-ol according to conditions described in general procedure D. A pink " solid is produced(20 mg).
  • Compound B182 Compound is prepared from tert-butyl (4-hydroxy-l-naphthyl)carbamate, 3-fluoro-5-piperidin-l-yl-benzoic acid and l-(3-hydroxy-propyl)-pyrrolidin-2-one according to conditions described in general procedure D. A pink solid is produced (42 mg).
  • Compound B50 7V-[4-(2-Morpholin-4-ylcthoxy)-l-naphthyl]-l,2,3-benzothiadiazole-5-carboxamide (Compound B50).
  • Compound is prepared from benzo[l,2,3]thiadiazole-5-carboxylic acid and 4-(2-mo ⁇ holin-4-yl-ethoxy)-naphthalen-l-ylamine according to conditions described in general procedure G.
  • the mixture is diluted with CHCl 3 (5 ml) washed with sat'd NaHCO 3 solution (5 ml), water (5 ml), dried over Na 2 SO 4 and concentrated to give a yellow solid.
  • the yellow solid is mixed with N,N,2,2-tetramethyl-l,3-propanediamine (1.18 g, 9.08 mmol) and DIPA (1.58 ml, 9.08 mmol) in DMSO (2ml), and heated to 85 0 C for 4 h.
  • the resulting mixture is diluted with CH 2 Cl 2 (2 ml), washed with 0.01 N NaOH, dried over Na 2 SO 4 , concentrated.
  • 4-(2-Morpholin-4-yl-ethoxy)-naphthalen-l-ylamine A mixture of 4-nitro-l-(2- morpholinethoxy)naphthalene (10 g, 33.0 mmol), methanol (80 ml) and Pd/C (10%, 1 g) is shaken under hydrogen at 30 psi for 4 hours. The catalyst is removed by filtration through a bed of Celite ® under a stream of nitrogen. The filtrate is evaporated to dryness to give 4-(2- morpholin-4-yl-ethoxy)-naphthalen-l-ylamine (7.32 g, 81.3 %).
  • 3-Bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthaIen-l-yl]-benzamide 3-Bromobenzoic acid (1.66 g, 8.2 mmol), 4-amino-l-(2-morpholinethoxy)naphthalene (1.5 g, 5.5 mmol) and HBTU (3.13 g, 8.2 mmol) are dissolved in anhydrous dimethylformamide (2 ml). Diisopropylethyl amine (2.0 ml, 11.0 mmol) is then added and the mixture agitated at room temperature overnight.
  • Biphenyl-3-carboxylic acid [4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-amide (Compound B84). Compound is prepared from 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-benzamide and phenyl boronic acid according to conditions described in general procedure K.
  • N-(4-Boronic acid-naphthaIen-l-yl)-3-fluoro-5-morpholin-4-yl-benzainide To a -78 0 C solution of N-(4-bromo-naphthalen-l-yl)-3-fluoro-5-morpholin-4-yl-benzamide (1.0 g, 2.33 mmol) in dry THF (30 ml) under a stream of argon is added nBuLi (1.6M in THF, 3.2 ml, 5.14 mmol). The mixture is stirred for 5 minutes before adding triisopropylborate (0.646 ml, 2.80 mmol).
  • Methyl Z-chloro- ⁇ -morpholin- ⁇ ylpyrimidine ⁇ -carboxylate To a solution of 2,6- dichloropyrimidine-4-carboxylic acid methyl ester (300 mg, 1.45 mmol) in dimethylsulfoxide (2 ml) is added morpholine (0.126 g, 1.0 eq) followed by diisopropylethylamine (0.285 ml, 1.1 eq). The mixture is stirred at room temperature for 15 diluted with water and extracted with ethyl acetate (2 x 20 ml). The combined organic layers are washed with water, dried over Na 2 SO 4 and evaporated to dryness.
  • 2-Chloro-6-morpholin-4-ylpyrimidine-4-carboxylic acid A suspension of methyl 2-chloro- 6-morpholin-4-ylpyrimidine-4-carboxylate (0.30 g, 1.16 mmol) in a mixture of THF:H 2 O:MeOH (12 ml, 4:1 :1) is stirred at room temperature for 24 hrs with lithium hydroxide (28 mg, 1.0 eq). The mixture is then evaporated to dryness to give 2-chloro-6-morpholin-4- ylpyrimidine-4-carboxylic acid as a solid (280 mg).
  • A- (2-Mo ⁇ holin-4-yl-ethoxy)-naphthalen-l-ylamine (0.224 g, 0.82 mmol) is then added.
  • the mixture is stirred at room temperature for an additional 15 h, diluted with water and extracted with ethyl acetate.
  • the organic layer is dried over Na 2 SO 4 and evaporated to dryness.
  • the residue is purified by column chromatography on silica gel eluted with 2% MeOH in ethyl acetate to provide 2-chloro-6-morpholin-4-yl-pyrimidine-4-carboxylic acid [4-(2-morpholin-4- yl-ethoxy)-naphthalen-l-yl] -amide as a solid (0.342 g).
  • 6-Morpholin-4-yl-pyrimidine-4-carboxylic acid [4-(2-morpholin-4-yl-ethoxy)- ⁇ aphthalen- l-yl]-amide (Compound B54).
  • 2-chloro-6-morpholin-4-yl-pyrimidine-4- carboxylic acid [4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl] -amide (95 mg) and 10% Pd/C (10 mg) in ethyl acetate (4 ml) is added a few drops of triethylamine.
  • the mixture is then shaken at room temperature under hydrogen at 50 psi for 8 h.
  • 3-Fluoro-5-morpholin-4-yl-N-[4-(3-morphoIin-4-yl-propyl)-naphthalen-l-yl]-benzamide (Compound B240). 3-Fluoro-5-morpholin-4-yl-N-[4-(3-morpholin-4-yl-propenyl)-naphthalen- l-yl]-benzamide (56 mg, 117 ⁇ mol), is stirred under 1 atmosphere of hydrogen with 10% palladium on carbon (50 mg) in methanol (15 ml) at room temperature for 1 day. Celite ® (1 g) is then added and the mixture filtered through a pad of Celite® and washed with methanol (2x10 ml).
  • aqueous layer is re-extracted with ethyl acetate (2x100 ml), the organic layers combined and dried over anhydrous sodium sulfate.
  • the organic layers are evaporated to dryness and the residue purified by column chromatography on silica gel eluted with 20% ethyl acetate in hexanes to give [4-(2-chloro-ethoxy)-naphthalen-l- yl]-carbamic acid tert-butyl ester (1.448 g).
  • N-[4-(2-ChIoroethoxy)-naphthalen-l-yl]-3-fluoro-5-piperidin-l-yl-benzamide 4-(2- Chloroethoxy)-naphthalen-l-ylamine hydrochloride salt (482 mg, 1.86 mmol), 3-fluoro-5- piperidinylbenzoic acid (500 mg, 2.2 mmol), diisopropylethylamine (1.14 ml, 6.7 mmol) and HBTU (1.06 g, 2.8 mmol) are stirred at room temperature in anhydrous dimethylformamide (10 ml) for 1 day.
  • Compound B160 Compound is prepared from N-[4-(2- chloroethoxy)-naphthalen- 1 -yl]-3-fluoro-5-piperidin-l -yl-benzamide and piperidine-4- carboxylic acid ethyl ester according to conditions described in general procedure N.
  • N-(4-Bromo-naphthalen-l-yI)-3-fluoro-5-morpholin-4-yl-benzamide 3-Fluoro-5- morpholin-4-yl -benzoic acid (4.45 g, 19.8 mmol) and HBTU (8.19 g, 21.6 mmol) are stirred at room temperature in dry DMF (40 ml) for 1 hour.
  • 4-Bromo-naphthalen-l-ylamine (4.0 g, 18.0 mmol) and diisopropylethylamine (4.8 ml, 27 mmol) are then added and the mixture is stirred at room temperature for 16 hours.
  • N-( Q4-Bromo- naphthalen-l-yl)-3-fluoro-5-morpholin-4-yl-benzamide (2.5 g, 5.8 mmol), 1-hexenyl boronic acid (1.06 g, 8.3 mmol), cesium carbonate (3.04 g, 9.34 mmol) and tetrakis triphenylphosphine palladium(O) (100 mg) in dioxane (22 ml) are heated to 100 0 C under nitrogen for 24 hours.
  • Compounds of the invention are screened for the ability to inhibit ATF2 phosphorylation by p38 MAP Kinase in vitro.
  • the ability of compounds to inhibit ATF2 pho ' sphorylafiorRn ⁇ Ms' ' in vitro assay is correlated with the inhibition of p38 MAP Kinase and TNF ⁇ expression in vivo, and is therefore an indicator of potential in vivo therapeutic activity (Raingeaud, J., et al, J. Biol. Chem., 270: 7420-7426, 1995, Brinkman, M. N., et al, J. Biol. Chem. 274: 30882-30886, 1999 and Fuchs, S. Y. et al, J. Biol. Chem. 275: 12560-12564, 2000).
  • Materials: All kinases and the substrate ATF2 are acquired from Upstate Biotechnology
  • p38 MAP Kinases are recombinant human full-length proteins with an amino-terminal GST fusion, expressed in and purified from E. coli.
  • ATF2 is a GST fusion protein containing amino acids 19-96 of human ATF2 expressed in E. coli. All proteins are aliquoted and stored at -80 0 C.
  • p38 MAP Kinase assays are performed using an assay buffer containing 25 mM HEPES, pH 7.5, 10 mM MgCl 2 , 2 mM DTT, 20 mM ⁇ -glycerophosphate, 0.1 mM Na 3 VO 4 , 40 ⁇ M ATP and 1.25 ⁇ M of ATF2 and in the absence or presence of 1% human serum albumin, Method I and II, respectively, with 0.4-6ng of protein depending on the kinase used.
  • Compounds are serially diluted in DMSO and 2 ⁇ L of test compound at 25x final concentration is used. The vehicle control receives DMSO only.
  • Test compounds are pre-incubated with 20 ⁇ l of enzyme in kinase buffer (25 mM HEPES, pH 7.5, 10 mM MgCl 2 , 2 mM DTT, 20 mM ⁇ - glycerophosphate, 0.1 mM Na 3 VO 4 in the absence or presence of 1% human serum albumin, Method I and II, respectively) at room temperature for 15 minutes. Reactions are initiated by addition of 30 ⁇ l substrate solution to yield a final concentration of 40 ⁇ M ATP and 1.25 ⁇ M ATF2 in kinase buffer. The reactions are incubated for 30 minutes at 37 0 C and terminated by the addition of 18 ⁇ l of 200 mM EDTA.
  • kinase buffer 25 mM HEPES, pH 7.5, 10 mM MgCl 2 , 2 mM DTT, 20 mM ⁇ - glycerophosphate, 0.1 mM Na 3 VO 4 in the absence or presence of 1%
  • An ELISA method (I or II) is used to measure the phosphorylation of ATF2 at Thr 69.
  • Method I 96-well high binding plates (Corning 3369) are coated with 50 ⁇ l of kinase reaction for 1 hour at 37 0 C. The coated plates are washed with 200 ⁇ l washing buffer (25 mM Tris HCl, pH 8.3, 192 mM glycine, 0.1%SDS and 0.05% Tween-20) three times. The plates are then washed three times with SuperBlock in TBS (Pierce, 37535).
  • plates are incubated with 50 ⁇ l of rabbit anti-phospho-ATF2 antibody (Cell Signaling, 9221L, 1 :500) for 30 minutes at 37 0 C. Plates are washed three times with washing buffer prior to incubation with 50 ⁇ l HRP -conjugated goat anti-rabbit antibody (Cell Signaling, 7074, 1 :500) for 30 minutes at 37°C. Plates are then washed three times with washing buffer before incubation with 50 ⁇ l of Ultra TMB-ELISA (Pierce, 34028) for 8 minutes at room temperature. Finally, 50 ul of phosphoric acid (1 M) is added to stop reactions and plate absorbance is read at 450 run on a SpectraMax 250 plate reader.
  • rabbit anti-phospho-ATF2 antibody Cell Signaling, 9221L, 1 :500
  • Method II 96-well high binding plates (Corning 3369) are coated with 400 ng of monoclonal antibody against GST-tag (Cell signaling) in 100 ⁇ l containing sodium borate (pH 8.3) for 90 minutes at 37 0 C.
  • the plates are' ⁇ vashed w ⁇ tti'200 ⁇ fl washing buffer (25 mM Tris HCl, pH 7.2, 150 mM NaCl and Tween- 20) three times and blocked with 200 ⁇ l of 5% nonfat milk for 30 minutes at room temperature.
  • the plates are washed three times with washing buffer, 50 ⁇ l of stopped kinase reaction are added to each well and incubated for 80 minutes at 37 0 C.
  • the plates are washed three times with 200 ⁇ l washing buffer, and the plates are incubated with 50 ⁇ l of rabbit anti-phospho- ATF2 antibody (Cell Signaling, 922 IL, 1 :500) for 30 minutes at 37 0 C. Plates are washed three times with washing buffer prior to incubation with 50 ⁇ l HRP -conjugated goat anti-rabbit antibody (Cell Signaling, 7074, 1 :500) for 30 minutes at 37 0 C. Plates are washed three times with washing buffer before incubation with 50 ⁇ l of Ultra TMB-ELISA (Pierce, 34028) for 25 minutes at room temperature. Finally, 50 ⁇ l of phosphoric acid (1 M) is added to stop reactions and plate absorbance is read at 450 run on a SpectraMax 250 plate reader.
  • rabbit anti-phospho- ATF2 antibody Cell Signaling, 922 IL, 1 :500
  • HRP -conjugated goat anti-rabbit antibody Cell Signaling, 7074, 1
  • Results of the p38 ⁇ assay for certain compounds of the invention are shown in Table 1. It is found that compounds of the invention inhibit the phosphorylation of ATF2 in this in vitro assay. Preferred compounds exhibit IC 50 values of less than 500 nM, more preferably less than 100 nM, and still more preferably less than 20 nM.
  • Compounds of the invention are screened for the ability to inhibit TNF ⁇ and IL-I ⁇ release from THP-I cells stimulated with lipopolysaccharide (LPS) in vitro.
  • LPS lipopolysaccharide
  • the ability of compounds to inhibit TNF ⁇ and IL- l ⁇ release in this in vitro assay is correlated with the inhibition of p38 activity and TNF ⁇ and IL- l ⁇ expression in vivo, and is therefore an indicator of potential in vivo therapeutic activity (Lee J. C. et al, Ann. N.Y. Acad. Sci. 696: 149-170, 1993 and Nature, 372: 739-746, 1994).
  • THP-I cells from ATCC are maintained at 37 0 C, 5% CO 2 in RPMI 1640 media (available from MediaTech, Herndon, VA) containing 4.5 g/L glucose, supplemented with 10% fetal bovine serum, 1% penicillin/streptomycin and 50 ⁇ M ⁇ - mercaptoethanol.
  • Test compounds are initially dissolved in RPMI media with 1% DMSO (v/v). Compounds are then serially diluted in RPMI media for all subsequent dilutions. The assay is performed under sterile conditions. THP-I cells at a culture density of 6-8 x 10 5 cells/ml are collected and resuspended in the RPMI media at 10 6 cells/ml containing 10% fetal bovine serum, no serum or 1% human serum albumin (HSA). 100 ⁇ l of resuspended cells are added to each well, which contain 100 ⁇ l of a test compound. Test compounds are prepared at twice the final concentration. Final DMSO concentration is no more than 0.5 % (v/v).
  • LPS lipopolysaccharide
  • TNF ⁇ and IL- l ⁇ levels are measured using ELISA kits from Biosource (Catalog no. KHC3012 for TNF ⁇ ; KACl 192 for IL-l ⁇ ).
  • a SpectraMAX 250 is used as the plate reader. Analysis is performed by non-linear regression to generate a dose response curve.
  • the calculated IC 50 value is the concentration of the test compound that causes a 50 % decrease in TNF ⁇ or IL-l ⁇ levels.
  • TNF ⁇ inhibition data for certain compounds of the invention are shown in Table 1.
  • Preferred compounds exhibit IC 50 values for TNF ⁇ and/or IL- l ⁇ of less than 1000 nM, more preferably less than 200 nM, still more preferably less than 100 nM, and still more preferably less than 20 nM
  • Compounds of the invention are screened for the ability to inhibit the release of TNF ⁇ in an in vivo animal model.
  • Griswold D. E. et al Drugs Exp. Clin. Res. 19: 243-248, 1993, Badger, A.M. et al, J. Pharmacol. Exp. Ther., 279: 1453-1461, 1996, Dong, C. et al, Annu. Rev. Immunol., 20: 55-72, 2002 (and references cited therein), Ono, K. and Han, J., Cellular Signalling, 12: 1-13, 2000 (and references cited therein) and Griffiths, J. B. et al, Curr. Rheumatol. Rep., 1 : 139-148, 1999).
  • TNF ⁇ inhibition in this model is due to inhibition of p38 MAP kinase by the compound.
  • mice Male Sprague-Dawley rats (0.2 - 0.35 kg), female Lewis rats (0.13 - 0.15 kg) or male Swiss Webster mice (20 - 25 gm) are randomly divided into groups of six or more and are dosed intravenously by infusion or bolus injection, or are dosed orally with test compounds in a suitable formulation in each case. Thirty minutes following end of infusion or bolus injection, and 1-2 hr following oral administration, lipopolysaccharide E. c ⁇ ///0127:B8 (0.8 - 2 mg/kg) is administered IV. Blood samples are collected 1.5 hours post-treatment with LPS.
  • Serum TNF ⁇ levels are determined using the ELISA kit from Biosource (KRC3011C) and compared to that from vehicle-treated control.
  • kesulis Preferred compounds of the invention inhibit the release of TNF ⁇ in this in vivo assay.
  • Preferred compounds delivered intravenously exhibit an ED 50 value of less than 30mg/kg, more preferably less than 10mg/kg, and still more preferably less than 5mg/kg.
  • Preferred compounds delivered orally exhibit an ED 50 value of less than 100mg/kg, more preferably less than 20mg/kg, and still more preferably less than lmg/ kg.

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Abstract

La présente invention concerne, de manière générale, des composés pouvant inhiber les P38, des méthodes d'inhibition des P38 in vivo ou in vitro, des diagnostics permettant de déterminer leur activité dans le traitement d'états associés aux P38 et/ou aux cytokines ainsi que des méthodes de traitement d'états associés à l'activité des P38 ou à l'activité des cytokines.
PCT/US2005/024441 2004-07-08 2005-07-08 Naphtalenes disubstitues en position 1,4 utilises comme inhibiteurs de map kinase p38 WO2006010082A1 (fr)

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